Oral dosage form for propiverine or its pharmaceutically acceptable salts with an extended release of the active ingredient

ABSTRACT

By suitable retardation oral pharmaceutical compositions containing propiverine or one or several pharmaceutically acceptable salts thereof in an amount of 4 mg to 60 mg propiverine and having a prolonged release of the active agent are produced. Preferably a blend of active agent and optionally one or more acidic substances having a pK a  value of less than 6.65 are provided with a retarding coating or are embedded in a matrix which is then optionally coated with further retarding layers.

[0001] The invention relates to novel oral dosage forms of propiverineor pharmaceutically acceptable salts thereof having a prolonged releaseof the active agent.

[0002] Propiverine—the chemical name of it is:2,2-diphenyl-2-(1-propoxy)acetic acid(1-methyl-piperid-4-yl)ester or oneof the pharmaceutically acceptable salts thereof are generally known forthe treatment of hypertonic functional states in the bladder region(over-active bladder) (see DE 2937589).

[0003] The bladderspasmolytic propiverine acts as an anticholinergic inthat it immobilises the cholinergic/muscarineric utilised smoothmusculature of the bladder by blocking of the corresponding receptors.Furthermore there is a directed influence on the calcium household ofthe cell in the meaning of an increase of the effect.

[0004] Propiverine in the form of its hydrochloride in rapidly releasingoral dosage forms in several preparations, e.g. Mictonorm®, has been onthe market for years. The dosage used so far of e.g. three times a dayof one pill of Mictonorm® at 15 mg propiverine-hydrochloride eachresults in relatively heavily fluctuating blood levels with repeateddaily peaks. Because of the anticholinergic effect of propiverinetypical anticholinergic side effects like and accommodation disordershave to be accepted with a rapid increase of the blood level. Thereforethese side effects limit the amount of the possible unit dose ofnon-modified, rapidly releasing dosage forms to 10-20 mg.

[0005] For a therapeutically active blood level of propiverine the exactcompliance up-take intervals are thus necessary, which lead to problems,in particular with elder patients who are the main group havinghypertonic functional states of the bladder.

[0006] For these reasons it is desirable to reduce the repeated doseeach day with all its known effects to a once a day dose having the sameor improved therapeutic effect.

[0007] In order to realise suitable oral dosage forms with asufficiently delayed release of the active agent and a therapeuticallyeffective blood level for an interval of 24 hours one has to take intoaccount that such formulations naturally release substantial portions ofits content of active agent in the lower intestine regions.

[0008] It is generally known from a pharmacokinetical point of view thatthe resorption rate essentially determines the temporary building-up ofa blood level and that the quantative extent of the resorption as wellas the half-life period of the substance in the organism decide whetherat the end of the dosage intervals, i.e. before administration of thenext dose, effective blood levels can be maintained. A sufficientresorption rate and a sufficient extent of the resorption of the activeagent over the whole region of the gastrointestinal tract with itsdifferent pH values are thus necessary.

[0009] The weak basic propiverine having a pK_(a) value of 7.35±0.1(water, 25° C.) according to general teachings should relatively badlyresorb in protonated form in the stomach, but as a base, i.e. as theweak basic neutral form, it should be relatively well resorbed in theintestinal tract.

[0010] Since, however, the inner surface of the intestine is coated witha microscopically thin layer of water the solubility and the lipophilityof the base to be resorbed are of decisive importance beside the acidbase properties of a substance.

[0011] The distribution coefficient and the solubility ofpropiverine-hydrochloride in dependence of the pH value are known(determination of the amount of propiverine in the aqueous phase viaHPLC).

[0012] Distribution Coefficient of Propiverine-Hydrochloride(1-Octanol/Water, 25° C.) K Log pH [mean values, measured three times][K] 1.0 22 1.3 5.0 13 1.1 6.0 227 2.4 6.5 884 2.9 6.8 6904 3.8 7.0 103464.0 7.2 15438 4.2 7.5 26068 4.4 8.0 52372 4.7

[0013] Solubility of Propiverine-Hydrochloride in Water TemperatureSolubility pH [° C.] [g/l] 5.8 24 >200 5.8 37 368 6.0 24 209 7.0 24 1.27.2 24 1.1

[0014] These physicochemical properties of propiverine-hydrochloride arethus not suitable for the realisation of a delayed (retarded)formulation since in the aqueous phase a sufficient solubility is onlygiven in the acidic region which is the unfavourable resorption regionfor propiverine because of its protonation. In the more favourable pHrange for resorption above a pH of 6.65 there is, however, practicallyinsolubility, and the lipophilic propiverine base precipitates.Furthermore it is known from practical experiences that with thebeginning precipitation of the base even smallest amounts ofpropiverine-hydrochloride are coated with insoluble propiverine base,and any further transition into the corresponding base ceases. Thissubstance properties of the propiverine-hydrochloride appear to renderthe realisation of a 12 or 24 hour depot not very promising. Because ofthese reasons mentioned, experiments for the realisation of transdermalsystems have failed (Biol. Pharm. Bull. 1995, 18(7), 968-975).

[0015] Furthermore it is known that propiverine shows an extraordinarilystrong first pass effect by monooxygenase to the undesirablepropiverine-N-oxide which puts a strain on the organism.Propiverine-N-oxide with its quaternary, permanently positive chargednitrogen is very well soluble in water (solubility of >127 to >99 g/l atpH=4.0-8.0) in the whole pH range in contrast to propiverine, and isthus worse to resorb.

[0016] The monooxygenases present in the intestine oxidise thepropiverine base present in equilibrium to the N-oxide. Therewith theexcretion of propiverine is possible via its water-soluble N-oxide. Thispharmacokinetic substance property of propiverine appears to make therealisation of a 24 hours depot releasing in the lower intestinesections with a therapeutically effective level or bioequivalence,respectively, not very promising with the rapid release dosage formcurrently on the market.

[0017] Apart from propiverine the tertiary amine oxybutynine andtolterodine are common standard in therapy for the treatment ofhypertonic functional states of the bladder. The half-time period as themain pharmacokinetic criterion is only 2-3 hours for the rapidlyreleasing dosage forms of oxybutynine and tolterodine currently on themarket, the half-time period for propiverine, however, is 15 hours.

[0018] By means of several galenic techniques oral dosage forms having adelayed release of the active agent have been realised for oxybutynine(U.S. Pat. No. 5,912,268, WO 9523593, WO 9612477, WO 9637202) andtolterodine (WO 0012069, WO 0027369).

[0019] In the case of propiverine such a dosage form appears to makelittle sense or the long half-life period may even be in conflict with asuccessful realisation of a therapeutically usable formulation.

[0020] For weak basic drugs oral dosage forms having a delayed releaseof the active agent generally form prior art as single-unit formulationand also as multiple-unit formulation.

[0021] In controlled releasing single-unit forms, for example matrixtablets, multiple-layer tablets, diffusion tablets, an additionaldiffusion control, for example by means of tartaric acid (Int. J. Pharm.1997, 157, 181-187) or by means of succinic acid (Pharm. Ind. 1991, 53,686-690) is achieved. When chewing such a monolithic form a high amountof active agent would be suddenly released despite of retardation, whichwould be problematic in the case of highly active anticholinergic agentswith respect to medicament security.

[0022] Multiple-unit dosage forms do not show these disadvantages andare also described for weakly basic drugs (Pharm. Ind. 1989, 51, 98-101,540-543; Pharm. Ind. 1991, 53, 69-73, 595-600, 778-785;Arzneim.-Forsch./Drug Res. 1998, 48, 540-604). Further technicalsolutions for pH-dependent and in the basic region badly solublecompounds exist for example for dipyridamol (EP 32562; EP 68191) and forbromohexine (EP 69259).

[0023] It is the object of the invention despite of physicochemical andpharmacokinetic properties of propiverine and its salts which seem to bedisadvantages, to produce oral dosage forms of said active agent havinga prolonged release for the first time, which independently of the pHvalue of the whole gastrointestinal tract, independently of potentialdisorders of the gastro and intestinal peristaltics as well asrelatively independently of inter- and intraindividual differences ofpatients show over a period of 24 hours a constant blood level which isclinically relevant for the treatment of an over-active bladder whichsimultaneously decreased rate of side effects.

[0024] The solution of the object according to the invention followsfrom the features of the independent claim. Advantageous embodiments aredefined in the dependent sub-claims.

[0025] According to a preferred ambodiment, the object is preferablysolved in that oral dosage forms are realised which contain propiverineand/or one pharmaceutically acceptable salt thereof in a therapeuticallyeffective amount, corresponding to 4 mg to 60 mg propiverine, and whichshow the following in vitro release rates—measured in 750 ml 0.1 NClduring the first hour and subsequently measured in 750 ml USP-buffer atpH=5.8 using the Ph. Eur. basket method at 100 rpm and 37° C.:  0-20%propiverine, released after  1 hour 10-45% propiverine, released after 3 hours 30-60% propiverine, released after  5 hours 40-75% propiverine,released after  7 hours 50-80% propiverine, released after  9 hours >60%propiverine, released after 12 hours, and particularly preferred 60-90%propiverine, released after 12 hours,

[0026] which show a clinically relevant blood level over a prolongedperiod of time, bioequivalence to the rapidly releasing preparationcurrently on the market, a reduced rate of side effects and finally animproved patient-compliance because of the possibility of a once a dayadministration.

[0027] For the first time disadvantages resulting from thephysicochemical and pharmacokinetic properties of the drug propiverineand prejudices resulting from the long half-life period have beenovercome and simultaneously a therapeutic progress has been achieved.

[0028] The preferred embodiments have generally in common that, apartfrom 4-60 mg propiverine, preferably 9-45 mg propiverine or theequivalent amount of pharmaceutically acceptable salts thereof, andoptionally an acidic substance having a pK_(a) value of less than 6.65,preferably of 1.8 to 6.5, is included, and these two components arecoated with one or more retarding (controlled releasing) layers,comprising a material insoluble in gastric fluid and insoluble inintestinal fluid and/or a material insoluble in gastric fluid andsoluble in intestinal fluid, and/or are embedded in a controlled releasematrix, which includes a swellable or insoluble material and which mayoptionally be coated with a material which is insoluble in gastric fluidand soluble or insoluble in intestinal fluid, respectively.

[0029] Oral dosage forms according to the invention can, however, alsobe realized without the addition of an acidic substance, on principle.

[0030] Apart from the active agent, the preferred inventive compositionsinclude at least one pharmaceutically acceptable organic or inorganicacid having a pK_(a) value of less than 6.65, in particular edibleorganic acids and pharmaceutically acceptable salts of multi-basicacids, for example citric acid, tartaric acid, succinic acid, adipicacid, ascorbic acid, fumaric acid, sodium or potassium hydrogentartrate,sodium or potassium dihydrogencitrate, di-sodium or di-potassiumhydrogencitrate etc., or mixtures of these acids and salts in a ratio of2:1 to 20:1, preferably of 3:1 to 10:1, referring to the molarequivalent ratio between the total amount of a monovalent acidicsubstance to propiverine or propiverine salt.

[0031] The addition of acid does not serve for the pH controlled releasehere but instead realises the pH independent solubility of propiverineand the salts thereof by forming a “quasi-ionpair” of propiverine andacid, leading to a sufficient release in the whole intestinal tract,independent from the kind of the propiverine salt present, for examplealso of salts of strong acids, like the hydrochloride. With the additionof the acid an over-saturated or concentrated aqueous drug solution ofpropiverine, respectively, is avoided which would lead to an immediateprecipitation of the insoluble propiverine base at pH values of morethan 7. Furthermore, because of its diffusion pressure the formedionpair produces an optimal release from the retarded particles andresults in an additional “protection” of the propiverine against toostrong N-oxidation by protonation and probably in an improved resorptionbehaviour of the physiologically self-adjusting equilibrium between theresorbable free propiverine base and the less resorbable protonatedform, which can be seen from the small standard deviations of thepharmacokinetic data of the inventive forms compared to the rapidlyreleasing commercial form.

[0032] The pH dependent or pH independent retarding, film-forming,matrix-forming materials or the materials used in release modifyingsystems are generally known to the person skilled in the art and arecommercially available, for example:

[0033] Polymers and copolymers of acrylic and/or methacrylic acidesters, like Eudragit®, of vinylacetates and vinylpyrrolidones, likeKollidon® VA 64

[0034] Cellulose ethers and cellulose esters, like Methocel® andAquacoat® and Tylose®

[0035] Alginates, like Kelacid®, Texamid®

[0036] Xanthanes, like Keltrol®, Rhodigel®, further polysaccharides ormodified polysaccharides, like Chitosan, Guargum and Gum arabicum

[0037] Polyvinylalcohols, like Mowiol®

[0038] Cellulose acetate phthalates, like Aquateric®

[0039] Mono-, di- and triglycerides, like Cutina®

[0040] Waxes, like montaneglycolwax—HOECHST or resins, like shellac

[0041] Proteins and modified proteins

[0042] The use of acidic adjuvants according to the invention incombination with retarding coatings and/or a retardant (controlledrelease) matrix allows the production of so-called multiple-unitformulations as well as of so-called single-unit formulations.

[0043] So-called multiple-unit formulations in the form of pellets are aparticularly preferred embodiment.

[0044] According to the invention these pellets can have a particle sizeof 0.1 to 2.5 mm, preferably 0.6 to 1.5 mm, and can then be filled intocapsules or sachets or can be compacted together with tablettingadjuvants into tablets, whereby these spheroid particles can be includedin same or different sizes in one formulation.

[0045] By combination of several technology steps spheroid particles ofacidic substances having a diameter of 0.1 to 2.0 mm, preferably of 0.5to 1.2 mm, are firstly prepared in a known manner, for examplesparticles of crystalline citric acid, tartaric acid etc., by use of afluidised bed method from suspensions consisting of adjuvants, likelactose, of dissolved acids, like for example citric acid, of binders,like for example polyvinylpyrrolidone, and of anti-adhesive agents, likefor example talcum.

[0046] In order to control the dissolution of the highly water-solubleedible acids or of the other acidic substances the rounded acid coresaccording to the invention are coated with a lacquer film, for examplein a fluidised bed.

[0047] The materials of the gastric fluid insoluble and pH dependentintestinal fluid soluble membranes, like Eudragit® S and Eudragit® L arecommonly known. The same is true for the optional addition of binders orplasticisers, like polyvinylpyrrolidone or triethylcitrate.

[0048] It could not be foreseen that in the case of propiverine or thesalts thereof such a lacquer film is extraordinarily advantageous forthe inventive forms. If this lacquer film is missing the diffusioncaused by a high diffusion pressure and being unhindered may result inan undesirable rapid release of propiverine even despite the retardingof the active agent containing particles and the subsequent gastricfluid resistant retarding of these particles, and may lead to asignificantly decreased amount of propiverine released in the furtherrelease behaviour caused by a premature depletion of the acid reservoir(Embodiment Example 7).

[0049] In the next technological step propiverine or one of the saltsthereof is applied in an amount as necessary in a principally knownmanner, for example in a fluidised bed, together with the addition ofadjuvants, adhesives and binders and further portions of the alreadymentioned acids or acidic substances in an alcoholic aqueous suspension.There is also the possibility to apply a micronised active agent with orwithout the addition of microcrystalline adjuvants and the acids oracidic substances as mentioned in powderform, after a previous sprayingof the retarded acid cores with an adhesive solution. The addition ofportions of the same or different acids in relation to the acid beingpresent in the coated acid core is advantageous in order to obtain aninitial dissolution/release by buffering the intestinal fluidpenetrating through the subsequent retarded coating.

[0050] For the inventive composition with a delayed release which iscontrolled until its end it is favourable to coat the retarded acid coreloaded with the active agent in a next technological step, with one ormore retardation (controlled release) coatings individually or as acombined mixture with or without a further addition of binders andadjuvants.

[0051] The gastric fluid insoluble, pH independent intestinal fluidinsoluble materials to be used according to the invention having varyinghigh permeability and the gastric fluid insoluble, pH dependentintestinal fluid soluble materials are commercially available, forexample Eudragit® RS, Eudragit® RL and Eudragit® S or Eudragit® L,respectively.

[0052] The optimum amounts of the individual components, for example thecomposition of the corresponding mixtures depend on several factors,like for example the desired retarding effect, the kind of theindividual retarding components having their specific solubility andpermeability, and the ratio of acidic substance to active agentpropiverine. These parameters vary completely independently from eachother and are of essential importance for the controlled andlong-lasting, prolonged release of the propiverine.

[0053] With the use of difficult in vitro and in vivo experimentsinvolving a discovered in vivo/in vitro correlation these problems couldbe solved. With the in vivo/in vitro correlation found it is possible,without difficult clinical in vivo experiments, to prepare dosage formsof propiverine according to the invention in any composition, by asimple determination of in vitro relese parameters. If the releasevalues determined correspond to the claimed realease ranges, this dosageform is clinically relevant.

[0054] It has surprisingly been found that it is favourable that in thecase of propiverine the retardation coating sprayed onto the activeagent containing acid cores does not dissolve in the resorbing part ofthe gastric and intestinal tract as long as practically the whole activeagent has diffused in a time-controlled manner in the form of its acidionpair. Advantageously this coating should retain the acid beingpresent in the core as long as the formation of the propiverine acidionpair has completely finished. If the coating prematurely solubilisesor if it leaks too much, the gastric fluid always being present in alarge excess penetrates into the interior of the particles andneutralises the acid being present there. Thus, because of the lowsolubility of the propiverine in the pH range of the gastric fluidpractically no active agent can be dissolved and diffuse from theparticles. The acid being present in the interior of the particleslowers the pH value of the penetrating intestinal fluid, and then formsthe corresponding ionpair. After that the solution of the propiverineacid ionpair being formed in the interior diffuses through the membraneinto the intestine. Although unfavourable pH conditions are againdominating here, obviously over-saturation phenomena occur, ensuring asufficient resorption of the per se hardly soluble active agent.Naturally the acid being present in the particles is furthermore reducedduring the course of the release so that actually a strong decrease inthe diffusing amount or in the release of propiverine should occur. Inorder to avoid the latter the retardation coating controlling therelease rate should preferably be “partially soluble” in the gastricfluid. The term “partially soluble” has to be understood in the meaningof a certain permeability or as a diffusion resistance, respectively.Further, said retardation coating should additionally guarantee that inthe interior of the particles acidic pH conditions are alwayspredominating and optionally occurring pH deviations caused by foodinfluences or by other influences are adjusted.

[0055] Even small deviations in the ratio of Eudragit® RS/Eudragit®RL/Eudragit® S lead to drastic changes of the release profiles. If theratio of Eudragit® RS/Eudragit® RL/Eudragit® S of 2:1:2 purely found bychance is slightly changed to a ratio of 1.5:1:2.5 (Example 9) thisreduction of the intestinal fluid insoluble component with lowpermeability (Eudragit® RS) and the increased portion of the intestinalfluid soluble material (Eudragit® S) leads to a faster release of theactive agent or to a heavy diffusion of the acidic component,respectively.

[0056] This effect may be explained as follows: Since the gastric fluidinsoluble, intestinal fluid soluble material of this coating isdissolved in the intestinal fluid after a certain residence time of theparticles in the intestinal fluid, a too heavy release in the upperintestinal tract is effectively suppressed with a ratio of Eudragit®RS/Eudragit® L/Eudragit® S of 2:1:2, and the release of the active agentis completely shifted to the medium and lower intestinal tracts. Thus,said retardation coating reduces the particularly rapid resorption inthe upper intestinal tract without reducing the total release of theactive agent from the particles. This leads indisputably to aprolongation of the release of the active agent.

[0057] In order to obtain a gastric fluid resistance and not too highinitial release values in the following or to further modify the releasecharacteristics, respectively, it is common practice in the art to applyfurther retardation coating with gastric fluid insoluble and intestinalfluid soluble materials, for example Eudragit® L or Eudragit® S,respectively.

[0058] Furthermore the retardation coatings used according to theinvention may contain typical adjuvants, like for example plasticisers,wetting agents and anti-adhesive agents. Examples for suitablepharmacologically secure plasticisers are glycerine triacetate,polyethyleneglycols and citric acid esters, like triethylcitrate. Theapplication of retardation coatings onto the active agent containingparticles may be done with methods known per se, for example in arapidly rotating vessel or by spraying the lacquers in fluidised bedprocesses. The subsequent drying of the pellets in order to remove theresidual solvents originating from the suspension is known from theprior art.

[0059] The retarded particles obtained which may be in the form ofretarded pellets, granules or compacted particles may be filled intocapsules or sachets, preferably hard gelatine capsules, as desired. Itis possible to blend particles having different delay levels and tooptionally also add non-delayed particles of the active agent as aso-called starting dose. The retarding particles may, however, becompacted together with tabletting adjuvants, like cellulose, lactose,magnesiumstearate and the like, into tablets. This is in particularpossible with retarding particles having a diameter below 1 mm withoutsubstantially damaging the retardation coatings. Such a tabletdecomposes in less than 1 minute and releases the propiverine retardingparticles in their inventive form—like the hard gelatine capsule does.

[0060] A further preferred embodiment of so-called multiple-unitformulations are granules and compact particles containing one or moreacidic substances apart from propiverine or one salt thereof which arenot embedded in a retarding matrix, but which only include this mixturetogether with one or more controlled release coatings, and which aresubsequently compacted into tablets.

[0061] These so-called spheroid tablet formulations are produced in thatpropiverine or one of the pharmaceutically acceptable salts thereof inthe inventive molar ratio with one or several acidic substances iscompacted under strong pressure together with spheronising agents, likefor example lactose, microcrystalline cellulose, hydroxypropylcellulose,with lubricating agents, like for example magnesiumstearate, and withfurther adjuvants, like for example polyvinylpyrrolidone, in amicrocrystalline form, for example with a particle size of less than0.25 mm, and is then once again broken and screened to a particle sizeof, for example, 0.5-1.5 mm, the fine fraction is once again compactedand these technological steps are repeated as long as the total mixtureof the granular particles have been transferred into the desired size.

[0062] Such granular particles may, however, also be produced by othermethods, for example by extrusion/spheronisation, apart from thecompacting method described.

[0063] In the following the granular particles are coated with generallyknown gastric fluid insoluble and intestinal fluid soluble and/orgastric fluid insoluble and intestinal fluid insoluble retarded agents,like for example Eudragit® NE, Eudragit® L etc. Generally knowntabletting adjuvants, like microcrystalline cellulose, crospovidone,polyvinylpyrrolidone, magnesiumstearate etc., are added, the total blendis thoroughly mixed and pressed into tablets. Furthermore the thusproduced tablets can be coated with suitable coatings, which may berelease modifying. Even in this case the retardation layers guaranteethe formation of a propiverine acid ionpair and its controlleddiffusion. Since the inventive formulations decompose in less than 5minutes and thereby release hundreds of retarded propiverine acidparticles the decomposition time does not have any influence on therelease behaviour.

[0064] In contrast to the so-called multiple-unit formulations based onpellets or spheroid particles, retarded preparations of propiverine mayalso be produced in any other way, for example as single-unitformulation.

[0065] In particular suitable release characteristics may be achieved bymatrix retardation, for example by means of a matrix tablet.

[0066] Preferably, however, also in this embodiment one of the alreadymentioned acidic substances is used and the acidic substance as well asthe active agent is embedded in the retarding matrix. The initiallymentioned acidic substances, polymers, doses and molar ratios of acidicsubstance in relation to propiverine are principally suitable.

[0067] For example, for the preparation of inventive matrix tabletspropiverine or one of the pharmaceutically acceptable salts thereof andoptionally one or several acidic substances in a molar ratio accordingto the invention are intimately blended with retarding, matrix-formingadjuvants, like for example cellulose ethers, cellulose esters,alginates, xanthanes, polyvinylalcohols, fats, waxes and furthertabletting adjuvants, like for example magnesiumstearate, inmicrocrystalline form with a particle size of preferably less than 0.25mm and pressed into tablets. In the case of propiverine and the saltsthereof it has been found that the selection of the acidic substancesmay be done independently from their solubility in water. Thus, forexample adipic acid which is more difficult to solubilise in water andalso the tartaric acid which is easier to solubilise in water result inequal release profiles when used according to the invention. Whencontacting these tablets with water, for example in the case of a matrixmade of alkylcelluloses, a highly viscose gel layer is immediatelyformed which reduces the diffusion of the formedpropiverine-acid-ionpair in accordance with the desired release rate.

[0068] Apart from the already described dosage form comprisingpropiverine, one or several acidic substances and retarding materials,there is also the possibility to delay the release of combinations ofpropiverine or one or several pharmaceutically acceptable salts thereofwith one or more other active agents in the same manner, independentfrom the fact whether the used combination agents are acidic substances,like in the case of the already mentioned ascorbic acid, or not.

[0069] The invention is further illustrated by means of the followingEmbodiment Examples without being restricted thereto.

EMBODIMENT EXAMPLES

[0070] All percentages provided refer to percent by weight (wt.-%),unless indicated otherwise.

Example 1 Pellet Formulation With Propiverine Hydrochloride—100% ReleaseAfter 15 Minutes

[0071] For the preparation of spherical citric acid cores 3.5 kg citricacid having a particle size of 0.7-1.0 mm (Roche) were sprayed at an airtemperature of 45° C. using 2-substance nozzles in a fluidised bed withan isopropanolic aqueous suspension consisting of 105 gpolyvinylpyrrolidone (Kollidon® K25), 35 g citric acid, 275 g lactose(Microtose®), 210 g talc, 1500 g 2-propanol and 300 g water and a totalyield of 4.060 kg (98.4% of the theoretical amount, referring to thesolvent-free material) of rounded citric acid pellets was obtained.

[0072] 3.75 kg of said rounded citric acid pellets are retarded with anisopropanolic aqueous suspension consisting of 600 g Eudragit® S12.5(corresponding to 75 g Eudragit® S), 600 g Eudragit® L 12.5(corresponding to 75 g Eudragit L), 20 g triethylcitrate, 100 g talc,1500 g 2-propanol and 300 g water in an analogous manner in the nexttechnology step. The total yield was 4.013 kg (99.8% of the theoreticalamount, referring to solvent-free material).

[0073] For application of the active agent 3.95 kg of the retardedcitric acid cores were sprayed in an analogous manner using 2-substancenozzles in the fluidised bed at 45° C. air feed temperature with anisopropanolic aqueous suspension of 1300 g of micronised propiverinehydrochloride, 280 g polyvinylpyrrolidone (Kollidon® K25), 50 g citricacid, 200 g talc, 50 g magnesiumstearate, 2100 g 2-propanol and 400 g ofwater. The total yield obtained was 5.772 kg of active agent containingpreviously retarded citric acid pellets (90% referring to solvent-freematerial).

[0074] The content of propiverine-hydrochloride in the pellets wasdetermined by means of the method described in Example 6 to be 20.9% andthe content of citric acid to be 59.8%. This corresponds to a molarratio of propiverine-hydrochloride to citric acid of 1:6.0.

[0075] From the substance amounts used a molar ratio ofpropiverine-hydrochloride/citric acid of 1:5.2 is calculated. Thisdifference may be explained by losses during spraying and abrasion.

[0076] For filling into capsules, 10 g of microfine talc was added to2000 g of the obtained pellets and mixed for 15 minutes. The releasedata were determined by means of the method described in Example 5 andare listed in the Table provided there.

[0077] Then the material is screened and the fraction having a particlesize of 0.7-1.25 mm in diameter (98.0%) is further processed. 215 mgpellets corresponding to 45 mg propiverine-hydrochloride were filledinto hard gelatine capsules and were used for the bioavailability study(Example 13).

Example 2 Pelletformulation With Propiverine Hydrochloride—About 50%Release After 3 Hours

[0078] For the preparation of spherical citric acid starter cores 3500 gcitric acid granules (Roche) having a particle size of 0.7-1.0 mm weresprayed in a technically equivalent manner as described in Example 1with a suspension consisting of 30 g polyvinylpyrrolidone (Kollidon®),10 g citric acid, 70 g lactose (Microse®) and 60 g talc in 340 g2-propanol and 75 g water in a fluidised bed. 3665 g of rounded citricacid pellets were obtained (99.7% of the theoretical amount, referringto the dry substance used)

[0079] In the next step 3660 g of the above described citric acidpellets were sprayed with a suspension consisting of 600 g Eudragit® S12.5 (75 g dry substance Eudragit® S), 600 g Eudragit L 12.5 (75 g drysubstance Eudragit® L), 20 g triethylcitrate and 100 g microfine talc in1500 g 2-propanol and 300 g water. The total yield was 3930 gcorresponding to 100%, referring to solvent-free material.

[0080] 3650 g of these pellets were sprayed in the above describedmanner with a suspension consisting of 1000 g micronisedpropiverine-hydrochloride, 215 g polyvinylpyrrolidone (Kollidon® K25),40 g citric acid, 155 g microfine talc and 40 g magnesiumstearate in2100 g 2-propanol and 310 g demineralised water. The total amountobtained was 5030 g of active agent pellets. This corresponds to a yieldof 98.6%, referring to dry mass.

[0081] In a next technology step 3500 g of these active agent pelletswere retarded in the fluidised bed at an air feed temperature of 40-45°C. by means of 2-substance nozzles with an isopropanolic aqueoussuspension of 420 g Eudragit® RL 12.5 (corresponding to 52.5 g Eudragit®RS dry mass), 420 g Eudragit® RL 12.5 (corresponding to 48.4 g EudragitRL dry mass), 560 g Eudragit® S 12.5 (corresponding to 75 g Eudragit® Sdry mass), 20 g triethylcitrate, 120 g talcum, 1400 g 2-propanol and 210g water, and were dried intensively in the fluidised bed. The totalyield obtained was 3815 g (100% of the theoretical amount, referring tosolvent-free material).

[0082] In the next step a suspension of 1392 g Eudragit® L 12.5, 16 gtriethylcitrate and 105 g microfine talc in 1135 g 2-propanol and 380 gwater were applied onto 2900 g of the retarded active agent pellets. Thetotal amount obtained was 3190 g pellets (99.8% of the theoreticalyield, referring to dry mass).

[0083] For further retardation of the pellets a suspension of 300 gEudragit® RL 12.5 (37.5 g dry mass), 4 g triethylcitrate, 35 g microfinetalc and 96.5 g magnesiumstearate in 1370 g 2-propanol and 340 g waterwas then applied onto 2500 g of the retarded active agent pellets. Thetotal amount obtained was 2583 g pellets corresponding to a yield of99.5% of the theoretical amount, referring to the dry mass.

[0084] Before filling into capsules 2500 g pellets were mixed with 12.5g microfine talc for 15 minutes and subsequently screened. 2425 g(96.5%) of the pellets have a particle size of 0.7-1.25 mm in diameter.

[0085] The content of propiverine-hydrochloride in the pellets wasdetermined according to the method described in Example 6 to be 13.7%.

[0086] The content of citric acid in said pellets was also determinedaccording to the method described in Example 6 to be 53.0%. Thiscorresponds to a molar ratio of propiverine-hydrochloride citric acid of1:8.1.

[0087] From the substance amounts used, a molar ratio ofpropiverine-hydrochloride to citric acid of 1:6.9 was calculated. Thisdifference may also be explained by losses during spraying and lossesthrough abrasion.

[0088] For the bioavailability study of Example 14, 328 mg pelletscorresponding to 45 mg propiverine-hydrochloride are filled into hardgelatine capsules. The release data were determined according to themethod described in Example 5 and are listed in the Table providedthere.

Example 3 Pellet Formulation With Propiverine Hydrochloride—About 20%Release After 3 Hours and About 80% Release After 10 Hours Example 3.1

[0089] Batch Size on a Technical Scale

[0090] In the same manner, the same batch size and in the samecomposition of substances as described in Example 1, once again 5638 g(96.7% of the theoretical amount, referring to solvent-free material) ofpropiverine-hydrochloride containing previously retarded citric acidpellets were obtained.

[0091] 2900 g of the above described active agent pellets were sprayedwith a suspension of 600 g Eudragit® RS 12.5 (75 g dry substanceEudragit® RS), 304 g Eudragit® RL 12.5 (38 g dry substance Eudragit®RL), 600 g Eudragit® S 12.5 (75 g dry substance Eudragit® S), 20 gtriethylcitrate and 120 g microfine talc in 1415 g 2-propanol and 220 gdemineralised water. The total amount was 3227 g retarded active agentpellets (corresponding to 100% of the theoretical yield, referring tosolvent-free material).

[0092] 3100 g of these pellets were then sprayed with a suspensionconsisting of 868 g Eudragit® S 12.5 (108.5 g Eudragit® S dry mass), 11g triethylcitrate, 65 g microfine talc, 840 g 2-propanol and 100 gwater. The total amount of pellets was 3285 g corresponding to 100% ofthe theoretical amount, referring to solvent-free pellets.

[0093] Before filling into capsules, 3200 g of the thus obtained pelletswere mixed with additional 16 g of microfine talc for 15 minutes andthen screened. The particle size fraction of 0.7 mm to 1.25 mm (3120 g,corresponding to 97% of the theoretical amount) shows an experimentallydetermined content of 18.8% propiverine-hydrochloride.

[0094] The content of citric acid in the pellets was determined by meansof the potentiometric titration as described in Example 6 to be 50.7%.

[0095] From the amounts experimentally determined follows a molar ratioof active agent to citric acid of 1:5.7.

[0096] The theoretical ratio calculated on the basis of the masses usedis 1:5.2. The difference may also be explained by losses during sprayingand losses through abrasion.

[0097] 240 mg of the above described pellets corresponding to 45 mgpropiverine-hydrochloride were filled into hard gelatine capsules andwere used for the bioavailability study of Example 14.

[0098] The release data were determined according to the methoddescribed in Example 5 and are listed in the table provided there.

Example 3.2

[0099] Batch Size in a Scale Relevant for Production

[0100] For the manufacture of citric acid cores as starter pellets 250.0kg citric acid granules (Roche) having a particle size between 0.7 mmand 1.0 mm were sprayed by means of 2-substance nozzles in the fluidisedbed with a suspension of 7.5 kg polyvinylpyrrolidone (Kollidon® K25),2.5 kg citric acid, 19.6 kg lactose and 15.0 kg microfine talc in 89.3kg 2-propanol and 19.6 kg demineralised water. By this method 282.0 kgspherical citric acid starter cores were obtained (95.7% of thetheoretical amount, referring to solvent-free material).

[0101] 200.0 kg of these starter cores were then sprayed in atechnically equivalent manner with a suspension of 4.0 kg Eudragit®S100, 4.0 kg Eudragit L100, 1.1 kg triethylcitrate and 5.3 kg microfinetalc in 94.0 kg 2-propanol and 11.0 kg demineralised water. The totalamount obtained was 214.0 kg corresponding to 99.8% of the theoreticalamount, referring to the dry mass used.

[0102] Through subsequent screening all pellets having a diameter ofless than 1.25 mm were isolated.

[0103] In the following technology step the thus obtained retardedstarter cores were sprayed in two steps with a suspension of 85.3 kgpropiverine-hydrochloride, 22.7 kg polyvinylpyrrolidone (Kollidon® K25),8.5 kg citric acid, I 1.1 kg microfine talc, 0.802 kg magnesiumstearate,165.5 kg 2-propanol and 48.2 kg demineralised water. The yield in bothsteps was 94.8%, referring to the dry mass used.

[0104] 243.0 kg of the active agent pellets thus obtained having anamount of 21.75% propiverine-hydrochloride were coated for purposes ofretardation in a fluidised bed with a suspension of 54.7 kg Eudragit® RS12.5 (6.7 kg Eudragit® RS dry substance), 27.8 kg Eudragit RL (3.4 kgEudragit® RL dry substance), 6.7 kg Eudragit® S100, 1.8 kgtriethylcitrate and 10.8 kg microfine talc in 207.3 kg 2-propanol and23.8 kg demineralised water. The yield was 99.2% of the theoreticalamount of solvent-free retarded particles.

[0105] 237.4 kg of the above described retarded active agent pelletswere coated in a fluidised bed with a suspension of 5.7 kg Eudragit®S100, 0.582 kg triethylcitrate and 3.5 kg microfine talcum in 44.6 kg2-propanol and 5.4 kg demineralised water.

[0106] The pellets were dried for 60 hours at 70° C. before filling intocapsules. 13.0 kg of the pellets were then mixed with 65 g talcum for 10minutes and subsequently screened over a 1.25 mm screen. 12.8 kg of saidpellet fraction having a particle size of less than 1.25 mm showed acontent of 18.8% of propiverine-hydrochloride and 49.8% of citric acid,determined according to the method described in Example 6. The molarratio of active agent to citric acid was 1:5.6.

[0107] 240 mg of the thus obtained pellets each, corresponding to 45 mgpropiverine-hydrochloride were filled into hard gelatine capsules andused for the bioequivalence study of Example 15.

[0108] The release of propiverine from the pellets was carried out underthe conditions as described in Example 5. The results are listed in theTable provided there.

Example 4 Pellet Formulation With Propiverine

[0109] 2400 g spherical citric acid cores which were produced in thesame manner as already described in Example 3.2 were coated in afluidised bed at an air feed temperature of 40-74° C. with a suspensionconsisting of 48 g Eudragit® S100, 48 g Eudragit L100, 13 gtriethylcitrate, 65 g microfine talcum, 1860 g isopropanol and 200 gwater.

[0110] 2500 g of the thus obtained retarded starter cores were sprayedunder the same technical conditions with a suspension of 828 gpropiverine base, 177 g polyvinylpyrrolidone (Kollidon® K25), 63 gcitric acid, 200 g microfine talcum and 32 g magnesiumstearate in 3100 g2-propanol and 400 g water. The total amount obtained was 3740 g activeagent pellets corresponding to 98.4% of the theoretical amount,referring to the dry substance used.

[0111] In the same manner 3250 g of the active agent pellets weresprayed with a suspension of 720 g Eudragit® RL 12.5 (90 g dry massEudragit® RS), 368 g Eudragit® RL 12.5 (46 g Eudragit® RL dry mass), 90g Eudragit® S100, 24 g triethylcitrate and 146 g microfine talcum in1930 g 2-propanol and 300 g demineralised water.

[0112] 3500 g of the thus obtained retarded active agent pellets weresprayed in the fluidised bed under identical conditions with asuspension consisting of 86 g Eudragit® S100, 9 g triethylcitrate, 52 gmicrofine talcum, 129.9 g 2-propanol and 80 g water.

[0113] The thus obtained pellets showed a content of 19.4% propiverineas well as a content of 40.4% citric acid as determined by the methodsdescribed in Example 6. This results in a molar ratio of active agent tocitric acid of 1:4.0.

[0114] The release of propiverine from the pellets was determined by themethod described in Example 5 and is indicated in the Table providedthere.

Example 5 Determination of the Release Data—Comparison of the ReleaseData of Examples 1-4, 7-13

[0115] The determination of the release of propiverine-hydrochloride orpropiverine, respectively, from all of the described oral dosage formswas made with the help of the basket apparatus as described in Ph. Eur.3, 2.93 at 100 rpm for 17 hours.

[0116] For this an amount of pellets corresponding to 45 mgpropiverine-hydrochloride each was weighed into 6 baskets. The releaseis carried out for one hour in 750 ml gastric fluid medium (0.1 Mhydrochloric acid solution) at 37° C. This medium is thrown away aftermeasurement of the 1 hour value and the release is then carried out in750 ml of an 50 mM potassium dihydrogenphosphate buffer at pH 5.8 at 37°C. for further 16 hours.

[0117] The quantification of propiverine-hydrochloride or propiverine,respectively, in the release medium is carried out by means of anon-line coupled UV/VIS-spectrophotometer. For the measurement therelease medium is pumped at predefined periods from each releasecontainer through polypropylen filters via a 6-channel tube pump intothe flow vessel of the UV/VIS-spectrophotometer. The measurement of theextinction is at 239 nm whereby the extinction at 247 nm is additionallydetermined as the background. For calculation of the amount ofpropiverine-hydrochloride/propiverine the extinction value at thebackground wavelength is subtracted from the extinction value at themeasurement wavelength.

[0118] The calculation of the release data is carried out in relation toone sample of a reference substance which is measured under the sameconditions in the UV/VIS-spectrometer. The amount ofpropiverine-hydrochloride or propiverine, respectively, which isreleased during the first hour in 0.1 M hydrochloric acid is added tothe further release values.

[0119] The release data obtained are shown in Tables 1 and 2 as the meanvalues of a six fold determination. TABELLE 1 Release ofpropiverine-hydrochloride/propiverine in percent - Examples 1-4(n.d.—not determined) Example 3.1 (Pellet) Example 3.2 (Pellet) Example1 (pellet) Example 2 (Pellet) Propiverine- Propiverine- Example 4(Pellet) Propiverine- Propiverine- hydrochloride- hydrochloride-Propiverine- Time hydrochloride- hydrochloride- 20% after 3 h, 80% 20%after 3 h, 80% 20% after 3 h, 70% [h] 100% after 15 min 50% after 3 hafter 10 h after 10 h after 10 h 0.08 103.06 n.d. n.d. n.d. n.d. 0.17101.41 n.d. n.d. n.d. n.d. 0.25 100.05 n.d. n.d. n.d. n.d. 0.5 n.d. 0.430.00 0.69 0.59 1 101.08 6.41 0.85 1.00 2.76 1.5 — 14.75 4.70 1.38 7.57 2— 23.92 10.01 5.26 13.01 3 — 42.07 22.65 20.61 23.64 4 — 57.78 35.8733.37 32.80 5 — 70.11 48.18 44.82 41.13 6 — 79.16 58.83 55.28 48.49 7 —85.44 67.55 64.15 54.84 8 — 89.62 74.38 71.03 60.66 9 — 92.29 79.5376.16 65.48 10 — 93.94 83.29 79.88 69.73 11 — 94.93 85.96 82.50 72.95 12— 95.51 87.80 84.58 75.78 13 — 95.83 89.03 86.22 78.33 14 — 96.01 89.8487.42 79.89 15 — 96.11 90.36 88.44 81.81 16 — 96.16 90.69 89.33 83.05 17— 96.19 90.89 90.04 85.78

[0120] TABELLE 2 Release of propiverine-hydrochloride/propiverine inpercent - Examples 7-12 (n.d.—not determined) Example 8 Example 9Example 10 Example 7 (Pellet) (Pellet) (Pellet) (Spheroidal Example 11Example 12 Example 13 Propiverine-HCl, Propiverine-HCl Propiverine-HCl,tablets) (gel matrix tablets) (gel matrix tablets) (gel matrix tablets)Time non-retarded citric citric acid Eudragit RS/RL/S Propiverine-HCl,Propiverine-HCl, Propiverine-HCl, Propiverine-HCl, [h] acid cores 1:121.5:1:2.5 citric acid tartaric acid adipic acid without acid 0.08 n.d.n.d. n.d. n.d. n.d. n.d. n.d. 0.17 n.d. n.d. n.d. n.d. n.d. n.d. n.d.0.25 n.d. n.d. n.d. n.d. n.d. n.d. n.d. 0.5 0.30 0.00 0.52 0.35 2.690.16 4.64 1 0.56 0.00 1.47 1.80 6.17 5.12 9.55 1.5 5.58 3.41 10.48 3.2611.08 10.66 15.63 2 17.42 8.80 28.60 6.41 14.54 14.61 20.38 3 37.1435.46 48.91 16.54 20.96 21.75 27.99 4 55.53 59.52 67.24 26.82 26.9228.23 34.34 5 63.46 78.80 78.84 38.45 32.43 34.29 39.52 6 68.17 83.2783.36 49.61 37.57 39.91 44.19 7 71.00 87.54 84.00 59.24 42.30 45.0348.25 8 73.81 90.13 84.82 65.53 46.75 49.95 52.14 9 75.90 91.38 85.5671.55 50.94 54.47 55.71 10 77.48 91.72 86.22 75.12 54.80 58.74 58.70 1177.81 92.01 86.90 77.83 58.33 62.73 61.81 12 78.26 92.42 87.72 80.6761.61 66.14 64.65 13 78.65 92.76 88.41 82.98 64.75 69.42 67.34 14 79.0093.10 89.19 84.82 67.61 72.58 69.71 15 79.46 93.51 89.75 85.36 70.3675.44 72.06 16 79.81 93.94 89.93 86.16 72.91 79.99 74.14 17 80.20 94.3290.26 86.40 75.33 80.49 76.74

Example 6 Determination of the Amount ofPropiverine/Propriverine-Hydrochloride Via HPLC and of Citric Acid ViaPotentiometric Titration and of 2-Propanol Via GC

[0121] 1. For a quantitative determination ofpropiverine/propiverne-hydrochloride in varying dosage forms adrug-specific HPLC method is used which allows to separate matrixcomponents from analytes.

[0122] The method used provides correct results since it is valid withrespect to its selectivity for the analyte, linearity in thepredetermined working range, correctness and precision, which could beshown by means of the above commonly known experiments.

[0123] For a quantitative determination ofpropiverine/propiverine-hydrochloride in the active agent containingdosage forms, for example an amount of the finely powdered dosage formcorresponding to 15.0 mg propiverine-hydrochloride is exactly weighedinto a 100 ml volumetric flask, mixed with 50 ml of methanol and onedrop of 0.1 M hydrochloric acid and then treated in an ultrasonic bathfor about 10 minutes. Then 40 ml water are added and the suspension isonce again treated for about 10 minutes in an ultrasonic bath. Aftercooling down to room temperature water is added up to the calibrationmark.

[0124] As the reference solution, 60.0 mg propiverine-hydrochloride areexactly weighed into a 100 ml volumetric flask, mixed with 50 ml ofmethanol and one drop of 0.1 M hydrochloric acid and then treated in anultrasonic bath for about 10 minutes. Then 40 ml of water are added andthe solution is once again treated in the ultrasonic bath for about 10minutes. After cooling down to room temperature water is added up to thecalibration mark.

[0125] The chromatography is then carried out with a commercialapparatus consisting of a pump, an autosampler, a column oven and aUV/VIS detector, at a flow rate of 1.0 ml/min, 40° C. column temperatureand a detection wavelength of 220 nm, whereby the running time is 5minutes and the amount of injected sample or reference solution,respectively, is 20 μl. As a stationary phase a reversed phase material(LiChrospher 60 Select B, 5 μm, 125×4 mm, from Merck) and a mobile phaseconsisting of 56 parts per volume of a 10 mM potassiumdihydrogenphosphate buffer, pH 1.0 (with 85% phosphoric acid) and 44parts per volume of acetonitrile are used.

[0126] The quantification of propiverine/propiverine-hydrochloride inthe sample is carried out as a double determination against thecorresponding peak in the chromatogram of the reference solution at thesame wavelength. The result is given in weight percent in the dosageform.

[0127] 2. The quantitative determination of citric acid in the variousdosage forms is carried out by potentiometric titration of the firstequivalence point of citric acid.

[0128] The method used has been validated with respect to itsspecificity, correctness and precision, whereby it could be shown thatadjuvants or propiverine-hydrochloride do not distort the result.

[0129] For carrying out the measurement 50.0 mg of the finely powdereddosage form were exactly weighed, mixed with 50 ml of demineralisedwater and then treated for about 5 minutes in an ultrasonic bath. Thenit was titrated to the first equivalence point with 0.1 M sodiumhydroxide solution.

[0130] 1 ml of sodium hydroxide solution consumed corresponds to 6.403mg citric acid.

[0131] 3. The quantitative determination of 2-propanol in the pelletformulations is carried out via gaschromatography. This method providescorrect results since it is valid with respect to its selectivity forthe analytes, the linearity in the predetermined working range, thecorrectness and the precision, which could be shown with commonly knownexperiments.

[0132] For determination of 2-propanol in the pellet formulations, 100mg of each form were weighed into different centrifuge tubes and 1.0 mlof dimethylformamide was added. Then the suspension was extracted for 2minutes in the ultrasonic bath, centrifuged for 3 minutes at 10,000 rpmand the solution was decanted into vials.

[0133] As a reference solution 100 mg of 2-propanol are weighed into a100 ml volumetric flask and filled up to 100 ml with dimethylformamide.2.5 ml of this solution are filled up to 50 ml with dimethylformamide(500 ppm, referring to the pellet mass in the sample solution).

[0134] The chromatography is conducted with a commonly used commercialgaschromatography apparatus having a split injection device, atemperature-adjustable column oven and a flame ionisation detector, andwhich is operated with helium as the carrier gas.

[0135] As the stationary phase for example a BTR-CW-column of 10 mlength, an inner diameter of 0.53 mm and a film thickness of 1.0 μm isused. At a column flow of 6 ml/min, an injection volume of 1 μl and acolumn temperature of 60° C. 2-propanol is eluated after about 0.6minutes.

[0136] The quantification of 2-propanol in the sample is done as adouble determination against the corresponding peak in the chromatogramof the reference solution. The result is given in ppm in the dosageform.

Example 7 Retardation of Citric Acid Spheroids

[0137] In the same manner as already described in Example 1 and with thesame batch size, 3990 g (corresponding to 96.7% of the theoreticalamount, referring to solvent-free material) of spherical citric acidcores are obtained.

[0138] For application of the active agent, 3650 g of the non-retardedspherical citric acid cores are sprayed at an air temperature of 45° C.by means of 2-substance nozzles in a fluidised bed with an isopropanolicaqueous suspension consisting of 1200 g propiverine-hydrochloride, 260 gpolyvinylpyrrolidone (Kollidon® K25), 45 g citric acid, 185 g talc, 45 gmagnesiumstearate, 1940 g 2-propanol and 370 g demineralised water. Thetotal yield obtained was 5250 g of an active agent containingnon-retarded citric acid pellets (97.5%, referring to solvent-freematerial).

[0139] In the next technology step 3500 g of the thus obtained activeagent pellets were sprayed in the fluidised bed at an air feedtemperature of 40-45° C. by means of 2-substance nozzles with anisopropanolic aqueous suspension of 720 g Eudragit® RS 12.5 (90 g drysubstance Eudragit® RS), 365 g Eudragit® RL 12.5 (corresponding to 45 gEudragit® RL dry substance), 720 g Eudragit® S 12.5 (90 g Eudragit® Sdry substance), 24 g triethylcitrate and 144 g microfine talc in 1700 g2-propanol and 264 g water. The total amount obtained was 3700 gretarded active agent pellets. This corresponds to a theoretical yieldof 95.0%, referring to the dry material.

[0140] 2800 g of the thus obtained pellets were sprayed under identicaltechnological conditions with a suspension of 781 g Eudragit® S 12.5(corresponding to 98 g Eudragit® S dry substance), 100 g triethylcitrateand 58.5 microfine talcum in 760 g 2-propanol and 90 g water. The totalamount of pellets obtained was 2960 g. This corresponds to a yield of100% of the theoretical amount, referring to solvent-free pellets.

[0141] Before filling into capsules, 2900 g of the thus obtained pelletswere mixed with 15 g talc and then screened. The particle size fractionof 0.7 mm to 1.25 mm (265.0 g, corresponding to 91% of the theoreticalamount) shows a content of 19.0% propiverine-hydrochloride as determinedaccording to Example 5. The content of citric acid was determinedaccording to the titration as described in Example 6 to be 53%.

[0142] The result from the experimentally determined amounts is a molarratio of active agent to citric acid of 1:5.8.

[0143] The release of propiverine-hydrochloride from the above describedpellets was determined by means of the method as illustrated in Example5. The results are listed in the Table provided there.

Example 8 Pellet Formulation With Propiverine-Hydrochloride—Molar Ratioof Active Agent to Citric Acid 1:12

[0144] In the same manner as already described in Example 1 and with thesame batch size 4019 g (corresponding to 97.4% of the theoreticalamount, referring to dried substance) spherical citric acid cores areobtained.

[0145] 3750 g of the thus obtained cores are retarded in the same manneras already described in Example 1 with an isopropanolic aqueoussuspension consisting of 600 g Eudragit® S 12.5 (corresponding to 75 gEudragit® S), 600 g Eudragit® L 12.5 (corresponding to 75 g Eudragit®L), 20 g triethylcitrate, 100 g talc, 1500 g 2-propanol and 300 g water.The total yield was 4000 g, corresponding to 99.5% of the theoreticalamount, referring to solvent-free material.

[0146] 3500 g of the thus obtained retarded citric acid spheroids aresprayed by means of2-substance nozzles in the fluidised bed at 45° C.air feed temperature with an isopropanolic aqueous suspension of 575 gpropiverine-hydrochloride, 250 g polyvinylpyrrolidone (Kollidon® K25),45 g citric acid, 175 g talc, 45 g magnesiumstearate, 1860 g 2-propanoland 350 g water. The total yield obtained was 4490 g of active agentpellets (corresponding to 97.8%, referring to solvent-free material).

[0147] 3500 g of the thus obtained active agent pellets were sprayedunder identical technological conditions with an isopropanolic aqueoussuspension consisting of 720 g Eudragit® RS 12.5 (corresponding to 90 gdry substance Eudragit® RS), 365 g Eudragit® RL 12.5 (corresponding to45 g Eudragit® RL dry substance), 720 g Eudragit® S 12.5 (correspondingto 90 g Eudragit® S dry substance), 24 g triethylcitrate and 144 gmicrofine talc in 1700 g 2-propanol and 264 g water (demineralised). Thetotal amount obtained was 3894 g of the retarded active agent pellets.This corresponds to a total yield of 100.0% of the theoretical amount,referring to the dry substance.

[0148] 3100 g of the thus obtained retarded active agent pellets werethen sprayed in the same manner with a suspension of 865 g Eudragit® S12.5 (108 g Eudragit® S dry substance), 110 g triethylcitrate, 65 g talcin 840 g 2-propanol and 100 g water. 3380 g of the double-coated activeagent pellets were obtained (99.9% of the theoretical amount, referringto solvent-free material).

[0149] Before filling in hard gelatine capsules, 3000 g of the thusobtained pellets were mixed under addition of 15 g talc and subsequentlyscreened. The particle size fraction of 0.7 mm to 1.25 mm (2750 g,corresponding to 91.7% of the theoretical amount) shows a content amountof 9.8% of propiverine-hydrochloride as determined according to Example6. The content of citric acid was determined by means of the titrationas described in Example 6 to be 55.2%. This results in a molar ratio ofactive agent to citric acid of 1:11.8.

[0150] The release of propiverine-hydrochloride from the above describedpellets was determined according to the method as illustrated in Example5. The results are listed in the Table provided there and show that therelease of the active agent is considerably reduced in the first andsecond hour, similar to Example 3.1. In the further course the higheramount of citric acid becomes, however, apparent, which results in ahigher osmotic pressure and thus in a more rapid release of the activeagent.

Example 9 Pellet Formulation With Propiverine-Hydrochloride—EudragitRatio RS/RL/S 1.5:1:2.5

[0151] In the same maimer as already described in Example 1 and with thesame batch size, 4000 g (corresponding to 97.0% of the theoreticalamount, referring to solvent-free material) spherical citric acid coresare obtained.

[0152] For retardation, 3750 g of the thus obtained starter cores aresprayed in the same manner with a suspension having the samequantitative composition as already described in Example 1. The totalamount of retarded citric acid cores was 3980 g which corresponds to ayield of 99.0%, referring to solvent-free material.

[0153] 3500 g of the thus obtained retarded citric acid spheroids aresprayed by means of 2-substance nozzles in the fluidised bed at 45° C.air feed temperature with an isopropanolic aqueous suspension of 1100 gpropiverine-hydrochloride, 250 g polyvinylpyrrolidone (Kollidon® K25),45 g citric acid, 125 g talc, 45 g magnesiumstearate, 1860 g 2-propanoland 350 g water. The yield obtained was 4490 g of active agent pellets(corresponding to 97.8%, referring to solvent-free material).

[0154] 4000 g of the thus obtained active agent pellets were sprayedunder identical technological conditions with an isopropanolic aqueoussuspension consisting of 615 g Eudragit® RS 12.5 (corresponding to 77 gEudragit® RS dry substance), 410 g Eudragit® RL 12.5 (corresponding to51 g Eudragit® RL dry substance), 1025 g Eudragit® S 12.5 (correspondingto 128 g Eudragit® S dry substance), 27 g triethylcitrate and 165 gmicrofine talc in 1950 g 2-propanol and 300 g water (demineralised). Thetotal amount obtained was 4440 g of the retarded active agent pellets.This corresponds to a total yield of 99.8% of the theoretical amount,referring to the dried substance.

[0155] 3100 g of the thus obtained retarded active agent pellets weresprayed in the same manner and with the same suspension as alreadydescribed in Example 8. Thereby 3100 g of the lacquered active agentpellets (91.5% yield of the theoretical amount, referring tosolvent-free material).

[0156] Before filling into hard gelatine capsules, 2500 g of the thusobtained lacquered active agent pellets were screened under addition of15 g microfine talc. The particle size fraction of 0.7 mm to 1.25 mm(2450 g, corresponding to 98.0% of the theoretical amount) has a contentof 18.5% of propiverine-hydrochloride as determined according to Example6. The content of citric acid was determined by means of the titrationas described in Example 6 to be 49%. Thus the result is a molar ratio ofpropiverine to citric acid of 1:5.6, which is in the typical range.

[0157] The release of propiverine-hydrochloride from the above describedlacquered pellets was determined according to the method illustrated inExample 5. The results of the release are also to be found there.

Example 10 Spheroid Tablet Formulation With Propiverine-Hydrochloride

[0158] For manufacturing a tablet from gastric fluid resistantspheroidal particles 1.25 kg propiverin hydrochloride (particle sizeless than 0.25 mm), 2.97 kg citric acid (particle size less than 0.25mm), 0.80 kg polyvinylpyrrolidone (Kollidon® K25), 1.44 kg lactose(Tablettose®) were mixed for 5 minutes in a double twist blender(Rhoenrad-blender). In order to clash agglomerates the mixture was puton a sieve with a mesh diameter of 0.81 mm and mixed for additional 5minutes. Then 0.05 kg of magnesiumstearate was added to this mixture viaa screen having a mesh size of 0.5 mm and the total mass was mixed forfurther 2 minutes. The mixture has a molar ratio of propiverinehydrochloride to citric acid of 1:5.

[0159] The thus obtained mixture was compacted and the obtainedparticles were subsequently broken. The fraction of 0.6-1.2 mm wasscreened. The resulting fine fraction was repeatedly compacted, brokenand screened until the total amount was present in granule particles ofthe size mentioned. The total yield was 5.28 kg, corresponding to 81.1%of the theoretical amount.

[0160] 3.5 kg of the obtained granule particles were sprayed in thefluidised bed with an aqueous suspension of 967 g Eudragit® NE 30 D(corresponding to 290 g dry mass), 467 g Eudragit® L 30D (correspondingto 140 g dry mass), 100 g talcum and 3300 g water with a 2-substancenozzle at an air feed temperature of 50° C. and subsequently dried at anair feed temperature of 40° C. at a reduced amount of air. The totalyield was 3.985 kg corresponding to 93.8% of the theoretical amount,referring to solvent-free material.

[0161] 3.0 kg of the thus obtained retarded particles were mixed in adouble twist blender (Rhoenrad-blender) with 5.0 kg of microcrystallinecellulose (type 101), 0.52 kg polyvinylpyrrolidone (Kollidon® K25) and1.0 kg crospovidone XL for 20 minutes. Then 0.1 kg of magnesiumstearatewere added to the mixture via a screen having a mesh size of 0.50 mm andit was again mixed for 5 minutes.

[0162] The thus obtained pressed mixture was pressed on a rotary presswith an oblong stamp tool (length 19 mm, width 8.5 mm, radius of thecurvature 8 mm) into tablets having a mass of 865 mg and a fracturestrength of 100-140 N.

[0163] By means of the methods described in Example 6 an account of 5.2%propiverine-hydrochloride and 11.8% of citric acid was determined. Thisresults in a molar ratio of active agent to citric acid of 1:4.8. Thisdifference may also be explained through abrasion losses and lossesduring spraying within the various technology steps.

[0164] The release of propiverine-hydrochloride from the above describedtablets was determined by means of the method as described in Example 5.The data found are listed in the Table provided there.

Example 11 Gel Matrix Tablet Formulation With Propiverine-Hydrochlorideand Tartaric Acid

[0165] For the manufacture of a gastric fluid resistant gel matrixtablet having propiverine-hydrochloride and tartaric acid, 132.5 gtartaric acid having a particle size of 100% less than 250 μm, 112.5 gpropiverine-hydrochloride, 187.5 g hypromellose (Methocel® K100) and62.5 g of mixrocrystalline cellulose were mixed for 10 minutes in adouble twist blender, put onto a sieve having a mesh diameter of 0.81 mmand again mixed for 10 minutes. One part of the blend is pre-rubbed with5.0 g of magnesiumstearate and the resulting abrated portion is added tothe rest of the premixture over a screen having a mesh size of 500 μm.Then it is mixed again for 2 minutes.

[0166] The blend thus obtained is pressed on a rotary press having an 8mm tool (radius of the curvature 9 mm) into tablet cores with a fracturestrength of 50 N-70 N and an abrasion of less than 0.5%.

[0167] 350 g of the thus obtained tablet cores are sprayed in thefluidised bed by means of 2-substance nozzles with a suspension of 48 gEudragit® L 12.5 (6.0 g Eudragit® L dry substance), 60 mgmagnesiumstearate, 600 mg talcum and 600 mg triethylcitrate in 40 g2-propanol.

[0168] 355 g of the gastric fluid resistant gel matrix tablets wereobtained, corresponding to a total yield of 99.4%.

[0169] The amount of propiverine-hydrochloride was determined by themethod as described in Example 6 to be 22.3%. This results in a molarratio of active agent to tartaric acid of 1:3.2. The release ofpropiverine-hydrochloride from the above described matrix tablets wasdetermined by the method according to Example 5 and it is listed in theTable provided there.

Example 12 Gel Matrix Tablet Formulation With Propiverine-Hydrochlorideand Adipic Acid

[0170] For the manufacture of a gastric fluid resistant gel matrixtablet with propiverine-hydrochloride and adipic acid, 132.5 g adipicacid having a particle size of 100% less than 250 μm, 112.5 gpropiverine-hydrochloride, 187.5 g hypromellose (Methocel® K100) and62.5 g of mixrocrystalline cellulose were mixed for 10 minutes in adouble twist blender, put onto a sieve having a mesh diameter of 0.81 mmand again mixed for 10 minutes. One part of the blend is pre-ribbed with5.0 g magnesiumstearate and the resulting abrated portion is added tothe rest of the premixture over a screen having a mesh size of 500 μm.Then it is mixed again for 2 minutes.

[0171] The blend thus obtained is pressed on a rotary press having an 8mm tool (radius of the curvature 9 mm) into tablet cores with a tensilestrength of 50 N-70 N and an abrasion of less than 0.5%.

[0172] 350 g of the thus obtained tablet cores are sprayed in thefluidised bed by means of 2-substance nozzles with a suspension of 48 gEudragit® L 12.5 (6.0 g Eudragit® L dry substance), 60 mgmagnesiumstearate, 600 mg talcum and 600 mg triethylcitrate in 40 g2-propanol.

[0173] 356 g of the gastric fluid resistant gel matrix tablets wereobtained, corresponding to a total yield of 99.46%.

[0174] The content of propiverine-hydrochloride was determined by themethod described in Example 6 to be 22.7%. This results in a molar ratioof active agent to adipic acid of 1:3.2. The release ofpropiverine-hydrochloride from the above described matrix tablets wasdetermined according to the method described in Example 5 and it islisted in the Table provided there.

Example 13 Gel Matrix Tablet Formulation With Propiverine-HydrochlorideWithout Addition of Acid

[0175] For the manufacture of a modified gel matrix tablet withpropiverine-hydrochloride and wihout acidic substances, 45 gpropiverine-hydrochloride having a particle size of less than 0.25 mm,247 g microcristalline cellulose (type 101) and 67 g hypromellose(Methocel® K100) were mixed for 10 minutes in a double twist blender,put onto a sieve having a mesh diameter of 0.25 mm and again mixed for10 minutes. One part of the blend is pre-rubbed with 3.6 gmagnesiumstearate and the resulting abraded portion is added to the restof the premixture over a screen having a mesh size of 0.25 mm. Then itis mixed again for 2 minutes in the double twist blender.

[0176] The blend thus obtained is pressed on a rotary tablet presshaving an 8 mm biconvex tool (radius of the curvature 9 mm) and abreaking kerf in the upper punch into tablet cores with a tensilestrength of 100 N-150 N, an average mass of 244 mg and an abrasion ofless than 0.5%.

[0177] 300 g of the thus obtained tablet cores are sprayed in thefluidised bed by means of 2-substance nozzles with a suspension of 40 gEudragit® L 12.5 (5.0 g Eudragit® L dry substance), 0.05 gmagnesiumstearate, 0.5 g talcum and 0.5 g triethylcitrate in 60 g2-propanol.

[0178] 304 g of the sprayed gel matrix tablets were obtained,corresponding to a total yield of 99%.

[0179] The content of propiverine-hydrochloride was determined by themethod described in Example 6 to be 12.2%. This results in a content of30.3 mg propiverine-hydrochloride per tablet. The content correction wastaken into account when calculationg the release. All other releaseparameters remained unchanged. The release release values found areincluded in the Table of Example 5 as mean values of a 6-timesdetermination.

Example 14 Comparative Bioavailability Study of Pellet Formulations ofExamples 1, 2 and 3.1

[0180] In a clinical study the bioavailability and the pharmacokineticsof the pellet formulations of Examples 1, 2 and 3.1 were compared witheach other.

[0181] For this purpose 6 test persons received the pellet formulationshaving 45 mg propiverine-hydrochloride each in a cross-over-design as asingle dose. The blood levels were observed in 25 time periods inintervals of 20 min-12 hours for 48 hours in total. Propiverine and itsmain metabolite propiverine-N-oxide were determined with a validatedHPLC method in the serum. For this 0.5 ml of the deep frozen serum orcontrol samples, respectively, were combined after defrosting with 0.5ml of phosphoric acid (4%) and then extracted by means of solid phases(Nexus cartridges, 1 ml, 30 mg). The eluates were evaporated to drynessand were taken up in 100:1 of mobile phase.

[0182] The chromatography was carried out on a commercially availableequipment consisting of a pump, an autosampler, a column oven and adiode array detector at a flowrate of 1.2 ml/min, a column temperatureof 40° C. and a detection wavelength of 202 nm, whereby the running timewas about 5 minutes and the amount of sample or reference solution,respectively (empty serum sample treated under the same conditions withaddition of propiverine-hydrochloride and propiverine-N-oxide) was 20μl. As the stationary phase a reversed phase material was used(pre-column: LiChrocart 10×2 mm, LiChrospher 60, RP-select B, 5 μm(Merck); separating column: LiChrospher 60-5, select B, 125×2 mm(Macherey-Nagel)) and as the mobile phase a mixture of 70 parts pervolume of acetonitrile and 30 parts per volume of phosphate buffer at pH7.3 (2 mM potassium dihydrogenphosphate and disodiumhydrogenphosphate)was used The registration and evaluation of the data was made by meansof a Chromeleon Chromatography Data System. Under these analyticconditions the finding for propiverine was 99% and forpropiverine-N-oxide 95%. At repeated measurements (n=5) of spiked serumsamples (10 ng/ml propiverine or 20 ng/ml N-oxide, respectively) thevariation coefficient of the measured concentrations was uniformly at6%.

[0183] With the measured concentrations concentration-time-curves (bloodlevels) over a time period of 48 hours were drawn up and the areabeneath these curves was calculated (Area Under the Curve=AUC). Thisparameter is a measure for the available amount of propiverine orpropiverine-N-oxide, respectively, available in the blood circulationover time (bioavailability).

[0184] The AUC-values obtained with this bioavailability study forpropiverine (see Table) show that a retardation of the drug release(Examples 2 and 3.1) does not result in a reduction of thebioavailability when compared with the immediately releasing pelletformulation (Example 1). Thus it is shown that by administration ofpropiverine in the form of the inventive retard formulations theavailability of propiverine even from lower intestinal tracts ismaintained. This means that with the release of propiverine in the lowerintestinal tract the reduction of bioavailability which is typicallyknown for basic drugs and which could be expected due to the knownphysicochemical properties of propiverine does not occur.

[0185] Contrary to the assumption that an unchanged propiverineresorption in the lower intestinal tracts may be the cause for this,surprisingly a reduced transformation to the propiverine-N-oxide(metabolite) was found as the reason. The amount (AUC) of the formedpropiverine-N-oxide or of the ratio of metabolite/mother substance,respectively, decreases with increasing retardation (see Table). Thus,with the administration of retarded oral dosage forms of propiverine orthe pharmaceutically acceptable salts thereof there is a reducedsystemic strain on the organism through the undesired metabolisationproduct propiverine-N-oxide at equal bioavailability of the active agentpropiverine.

[0186] It is clinically advantageous for an individual save dosage thatthe surprisingly discovered fact that the inter-individual variabilityof the amount of propiverine available (AUC), expressed as the variationcoefficient (VK), very significantly decreases with the retardation (seeTable). From 62% for the immediately releasing pellet formulation ofExample 1 a reduction to 27% for the formulation of Example 3.1, whichis the most retarded formulation, occurs.

[0187] In FIGS. 1 and 2 the concentration-time-courses (blood level) ofpropiverine or propiverine-N-oxide, respectively, after administrationof the pellet formulations of Examples 1, 2 and 3.1 are illustrated ascurves of the mean values of the 6 test persons. For comparativepurposes the blood level after administration of 3 pills (15 mgpropiverine-hydrochloride each) of the commercial product Mictonorm®(curves of the mean values of 34 test persons) are also illustrated. Itcan be seen that the pellet formulation of Example 1 may be taken as areference for the commercial product.

[0188] The blood levels in FIGS. 1 and 2 show that the retardationresults in a drastic reduction of the rate of the concentration increaseof propiverine and propiverine-N-oxide. Additionally the height of theconcentration maximum is reduced (Example 1 versus Example 2). Withstrong retardation, like in Example 3.1, a discrete concentrationmaximum can advantageously no longer be observed, i.e. a flattened bloodlevel having relatively constant concentrations for a long period oftime develops without decreasing the bioavailability by the retardation.

[0189] Furthermore it is noted that with the inventive dosage forms, forexample that of Example 3.1, and under observation of the in vitro/invivo correlation clinically effective blood levels can be realised for24 hours.

[0190] Additionally one may expect a decrease in the frequency and/orseverity of anticholinergic side effects caused by the avoidance ofconcentration peaks.

[0191] The results of the bioavailability study of the administration ofthe pellet formulations of Examples 1, 2 and 3.1 are illustrated in thefollowing Table as the mean values. TABLE Bioavailability (AUC) ofpropiverine and propiverine-N-oxide Pellet Pellet Pellet formulationformulation formulation Parameter Example 1 Example 2 Example 3.1Propiverine AUC_(0-48 h)[ng · h · ml⁻¹] 1667 1705 1596 VK[%] 62 47 27Propiverine-N-oxide 13076 8779 7829 AUC_(0-48 h)[ng · h · ml⁻¹]AUC-ratio 7.8:1 5.15:1 4.9:1 Propiverine-N- oxide/Propiverine AUC ofpropiverine- 100 71 63 N-oxide referring to Example 1[%]

Example 15 Bioequivalence Study of the Pellet Formulation of Example 3.2Compared to the Commercial Product Mictonorm®

[0192] In a bioequivalence study relevant for the admission andguideline-conformity the bioavailabiity of propiverine from the rapidlyreleasing commercial form (Mictonorm®) was compared with the pelletformulation of Example 3.2.

[0193] In doing so 12 male and 12 female healthy test persons receivedin a randomised manner in a cross-over-design over 7 days either 3 timesdaily one pill of Mictonorm® (15 mg propiverine-hydrochloride each) or 1daily the pellet formulation of Example 3.2 (45 mgpropiverine-hydrochloride). The change in medication took place after awashing-out phase of 14 days. At any seventh day the steady-state bloodlevels were observed in 28 time periods in intervals of 30 minutes—2hours for 24 hours in total. Propiverine and its metabolitepropiverine-N-oxide were determined in the serum by using the HPLCmethod as described in Example 13.

[0194] With the measured concentrations concentration time curves weredrawn up under the conditions of a repeated dose (steady-state bloodlevel) for a time period of 24 hours and the area beneath these curveswas calculated (Area Under the Curve=AUC_(0-24 h, ss)). This parameteris a measure for the amount of propiverine or propiverine-N-oxide,respectively, available in the blood circulation over 24 hours.

[0195] The results (see table data for bioequivalence) confirm theobservation already made in Example 13 also for steady-state conditions,where the bioavailability of propiverine remains unchanged when it isadministered in the form of retarded pellet formulations. There isbioequivalence between the commercial product (3×15 mg) and the pelletformulation of Example 3.2 (1×45 mg). Also the serum concentrationsaveraged over 24 hours are the same (see C_(average) in the Table).

[0196] Furthermore the advantage to be expected from Example 13 of areduced interindividual variability of the bioavailability ofpropiverine upon administration of the pellet formulation as compared tothe commercial product is confirmed. The variation coefficient for thepropiverine-AUC is only 15% for the pellet formulation (commercialproduct: 31%). Thus, an individualised dosage is clinically possible.

[0197] All 24 test persons show a decrease of the AUC of thepropiverine-N-oxide upon administration of the pellet formulationcompared to the commercial product in the intraindividual comparison.Thus, the result is a significantly smaller mean value of the AUC afteradministration of the pellet formulation compared to the commercialproduct. Also the averaged serum concentration over 24 hours issignificantly lower upon administration of the pellet formulation (seeC_(average) in the Table). Thus the reduction of the strains with theclinically not necessary transformation product propiverine-N-oxide asdescribed in Example 13 is confirmed for the conditions of the repeatedadministration (steady state).

[0198] The unchanged propiverine values for AUC and C_(average) uponadministration of the pellet formulation also prove that there is noaccumulation of propiverine in the meaning of a blood level increasewith time caused by the retarded release. TABLE Data of bioequivalencePellet formulation Mictonorm ® Example 3.2 Parameter 3 × 15 mg 1 × 45 mgPropiverine AUC_(0-24 h)[ng · h · ml⁻¹] 1677 1711  VK[%] 31  15Propiverine-N-oxide 11080 9316* AUC_(0-24 h)[ng·h·ml⁻¹] AUC-ratio 6.6:15.4:1 Propiverine-N- oxide/Propiverine AUC of propiverine-N-oxide 100 84* referring to Mictonorm ® [%] Propiverine 69.8   71.3C_(average)[ng/ml] Propiverine-N-oxide 462  388* C_(average)[ng/ml]

[0199] Apart from the data for bioavailability and pharmacokinetics theside effects were also recorded in this study. In the following Tablethe frequency of the side effects is listed, for which a connection withthe administration of propiverine has been classified by a physician as“safe”, “probably” or at least as “possible”. Upon the pelletformulation the frequency of the anticholinergic side effects typicalfor propiverine is reduced by nearly half (accommodation disorder andincreased sensitivity to light) or by a quarter (dryness in the mouth),respectively. The total frequency of all side effects reported isreduced by about one third. TABLE Side effects Pellet formulationMictonorm ® Example 3.2 Type of side effect (SE) 3 × 15 mg 1 × 45 mgAnticholinergic SE typical for propiverine: a) Accommodation disorder/19 10 (53%) increased sensitivity to light b) Dryness in the mouth 20 15(75%) Sum of other SE 12  8 (66%) Sum of all SE 51 33 (65%)

Example 16 In Vitro/In Vivo Correlation

[0200] For a simulation of the release processes of active agents fromvarious dosage forms the in vitro behaviour of the dosage forms iscorrelated with the in vivo data. If a correlation of the in vivo and invitro data can be shown, a prediction of the in vivo release behaviourof other dosage forms is possible due to their in vitro releasebehaviour.

[0201] As a first prerequisite for an in vivo/in vitro correlation onehas to demonstrate that the in vitro release mechanism is identical forthe dosage forms observed. This is shown by the homomorphy (homogeneityof forms) of the corresponding release profiles.

[0202] For this purpose the in vitro release data determined inaccordance with Example 5 for the propiverine-hydrochloride containingpellet formulations described in Example 2 and Example 3.1 areillustrated by means of a Weibull function:

[0203] M_((t))=M₀(1−e^({(λ·(t−τ})) ^(β) )

[0204] M_((t))=Amount of propiverine-hydrochloride released at time t

[0205] wherein M₀=Total amount released of propiverine-hydrochloride [%]

[0206] λ=Release constant [1/h]

[0207] β=Increase factor (s(ope)

[0208] τ=Shifting factor of the function on the time axis (lag-time) [h]

[0209] The adaptation of the curves was separately carried out for alldosage forms by means of a suitable software, for exampleHOEGIP-PC-Software, using the method of least error squares.

[0210] For the mathematical comparison of both in vitro release profilesthe curves were standardised to 100% propiverine-hydrochloride releasedat termination of the experiments. Subsequently the time values wereadapted by means of the following linear transformation:

[0211] t_(i,Ex2,trans)=(t_(i,Ex2)−τ_(Ex2))·(λ_(Ex2)/λ_(Ex3.1))+τ_(Ex3.1)

[0212] or

[0213]t_(i,Ex3,trans)=(t_(i,Ex3.1)−τ_(Ex3.1))·(λ_(Ex3.1)/λ_(Ex2))+τ_(Ex2)

[0214] wherein

[0215] t_(i,Ex2,trans)=Transformed time value of the i-th measured valueat time t_(i) of the dosage form according to Example 2

[0216] t_(i,Ex.2)=Not transformed time period of the i-th measured valueof the in vivo release of Example 2

[0217] τ_(Ex2)=Lag-time of the release of Example 2

[0218] λ_(P2)=Release contrasts of the measured values of the dosageform according to Example 2

[0219] The same is true for the indices of Example 3.1.

[0220] The results are illustrated in FIGS. 3 (transformation fromExample 2 to Example 3.1) and 4 (transformation from Example 3.1 toExample 2). The correlation coefficients for the transformation were0.9997 for the figure from Example 2 to Example 3.1 or 0.99969,

[0221] respectively, for the transformation from Example 3.1 to Example2. This value demonstrates the nearly exact homogeneity of form of thein vitro release profiles observed. The prerequisite for a comparison ofthe in vivo data with the in vitro data is thus given.

[0222] In a next step the average serum levels of propiverine from 6test persons after one administration of the dosage forms correspondingto Example 2 or Example 3.1, respectively, as already illustrated inExample 13, were added by means of the method of deconvolution to thecumulative in vivo release profile. For this purpose the active agentamounts available per time unit each in the serum are observed over timeconsidering the metabolic decomposition of the active agent.

[0223] Subseqently it was tried to depict the in vitro release profilesthus obtained by means of the linear transformation of the time axisalready described above onto the in vivo release profiles.

[0224] For the in vivo or in vitro release profiles, respectively, ofthe dosage forms corresponding to Examples 2 and 3.1 the results of thisprocedure are illustrated in FIGS. 5 and 6. It can be recognised thatthe curves illustrated show a good conformity of the release profilesfor both dosage forms observed. Thus, it could be demonstrated that thein vivo release profiles of Examples 2 and 3.1 can be determined bymeans of suitable in vitro release experiments. Therewith one may drawconclusions from the in vitro release profiles obtained to the in vivorelease ratio of dosage forms not tested with humans and theirusefulness for the production of clinically relevant blood levels andthus their relevance in practice can be predicted.

1-10. (Cancelled).
 11. A pharmaceutical composition for oraladministration having prolonged release of the active agent, containingpropiverine and/or one or more pharmaceutically acceptable saltsthereof, the composition having the following in vitro release, measuredin 750 ml of 0.1 N hydrochloric acid during the first hour andsubsequently measured in 750 ml USP buffer at pH=5.8 using a Ph. Eur.Basket method at 100 rpm and 37° C.:  0-20% propiverine, released after1 hour,  10-45% propiverine, released after 3 hours, 30-60% propiverine,released after 5 hours, 40-75% propiverine, released after 7 hours,50-80% propiverine, released after 9 hours, 60-90% propiverine, releasedafter 12 hours. 


12. The composition according to claim 1, wherein an amount of 4 mg to60 mg of propiverine or the corresponding equivalent amount of apropiverine salt or a mixture thereof is included.
 13. The compositionaccording to claim 1 additionally including at least one or more acidicsubstances having a pKa value of less than 6.65.
 14. The compositionaccording to claim 3, wherein the one or more acidic substances arepresent in an amount providing a ratio of 2:1 to 20:1 between the totalamount of acidic substance and the propiverine or propiverine salt ormixtures thereof is, said ratio determined as monovalent acidequivalents to moles of propiverine.
 15. The composition according toclaim 3 wherein the acidic substance comprises an edible organic acid, apharmaceutically acceptable salt of a multivalent acid, or a mixture oftwo or more of said acids and/or salts.
 16. The composition according toclaim 1 including at least one retarding agent.
 17. The compositionaccording to claim 1 in the form of a multiple-unit formulationcontaining particles, said particles comprising an, optionally retarded,acid-containing core, the core being coated with propiverine,propiverine salt or mixture thereof, optionally with further acidcomponents and adjuvants and the coated core being surrounded with aretardation layer made of generally gastric fluid and intestinal fluidinsoluble polymers or of a combination of gastric fluid and intestinalfluid insoluble polymers with gastric fluid insoluble but intestinalfluid soluble polymers respectively, and wherein the composition isfinally filled into capsules or sachets or is used as a component of asuspension for drinking.
 18. The composition according to claim 1 in theform of a multiple-unit formulation, comprising spheroidal tabletformulations, the spheroidal tablet formulations comprising granularparticles coated with gastric fluid insoluble but intestinal fluidinsoluble and/or intestinal fluid soluble material and being pressedinto tablets, wherein the granular particles are a compacted blend ofone or more of propiverine propiverine salts, one or more acidicsubstances, one or more spheronising agents, one or more lubricatingagents and one or more tabletting adjuvants, and wherein the tablets maybe additionally coated with retarding materials.
 19. The compositionaccording to claim 1 in the form of a single-unit formulation,comprising matrix tablet formulations, the matrix tablet formulationscomprising a blend of propiverine, propiverine salt or mixture thereof,optionally one or several acidic substances, and matrix-formingretarding adjuvants, the matrix tablet formulations being pressed intotablets, and wherein the formulation is optionally provided with acoating made of polymers of acrylic and/or methacrylic acid derivativesor cellulose ethers, cellulose esters, vinylacetates, vinylpyrrolidonesor shellac.
 20. A method of treating a hypertonic functional state ofthe bladder comprising administering a composition as in claim
 1. 21.The method of claim 20 wherein clinically relevant blood levels areachieved over a prolonged period of time.
 22. The method of claim 20wherein the composition is administered once a day.